The long-term success of lung transplantation is currently limited by the high incidence of transplant-related lung disease (Glanville, A. R., et al., 1987, Ann Intern Med 107:300-306; Trulock, E. P., 1993, Chest 103:1566-1576; Kesten, S., 1995, 152: 1321-1324; Paradis, I. et al., 1993, 14:751-763). This complication is related to the transplant recipients' ongoing immune response against donor major histocompatibility antigens. Such an immune response generally leads to persistent acute rejection of the lung allograft which is a predominant risk factor for the subsequent development of chronic rejection and permanent allograft dysfunction and failure resulting in excessive morbidity and mortality. This is a tragic consequence of lung transplantation and for this reason, is a leading area of research in this field. Although the rates of short-term survival after lung transplantation have improved compared to most other solid organ transplants, the therapeutic benefit of lung transplantation is still limited by poor longer-term outcomes principally due to chronic rejection of the transplanted lung.
Patients, whose lung allografts are in acute and/or chronic rejection, are currently treated by a variety of potent immunosuppressive agents, such as azathioprine, tacrolimus, mycophenolate mofetil and cyclosporine, generally given by the intravenous or oral route, that profoundly inhibit the T cell response to donor antigen within the transplanted allograft. Unfortunately, these immunosuppressive agents diminish the patient's ability to mount an effective response to viral, fungal and bacterial pathogens thereby predisposing the patient to life threatening opportunistic infections and other toxic events such as kidney toxicity. Despite usage of conventional systemic (oral or intravenous) immunosuppressive drugs, about 50% of the treated patients develop refractory chronic rejection, characterized histologically by bronchiolitis obliterans, followed by a progressive decline in pulmonary function and eventually respiratory failure and death.
Cyclosporine, an 11-amino acid cyclic polypeptide antibiotic is frequently used to prevent rejection after solid organ transplantation (Kahan, B. D., 1989, N Engl J. Med., 321:1725-1738; Kumar, M. S. A., et al., Transplant Proc., 20:407-413; Keenan R. J., et al., Transplantation 53:20-25). Cyclosporine acts as an immunosuppressive agent by selectively inhibiting immune responses mediated by T lymphocytes (Iacono, A. T., et al., 1997, Transplantation 64:263-269; Keenan, R. J., 1995, Surgery 118:385-391). Unfortunately, systemic cyclosporine has a narrow therapeutic index, e.g., ratio between toxic and therapeutic doses, and effective immunosuppressive doses often cannot be achieved due to the risk of toxicity to the liver and kidney. In addition, administration of systemic cyclosporine results in a high incidence of infections with viral, bacterial and fungal pathogens.
To date, oral cyclosporine, when combined with azathioprine (AZA) and prednisone, has proven incapable of persistently suppressing the alloresponse to the lung to an extent necessary to provide an optimistic long-term outcome (Griffith, B. P., 1992, Ann Thorac Surg 54:846-51). Other therapies for prevention of transplant rejection include anti-CD3 antibody (OKT3), methotrexate, lymphoid irradiation and mycophenolate mofetil. Unfortunately, even with these treatments clinical efficacy has been disappointing and associated with toxicity (Cahill, B. C., 1996, J Heart Lung Transplant 15:1130-1137; Valentine, V. G., et al., 1996, 109:1184-1189; Copeland, K. R. and Yatscoff, R. W., 13:281-288) Thus, cyclosporine either alone or as part of a multi drug immunosuppressive regimen has been imperfect in preventing both acute and chronic rejection.
Recent data has indicated that immunosuppression by local administration of cyclosporine may be beneficial. For example, using a collagen matrix impregnated with cyclosporine, it was demonstrated that controlled release of low dose cyclosporine, significantly prolonged non-heterologous heart allograft survival with negligible blood and kidney tissue cyclosporine concentrations (Bolling, et al., 1990, J Heart Transplant 9:74-78; Stepkowski, et al, 1989, Transplantation 47:17-23).
While most solid organ transplants are inaccessible to such localized immunosuppress therapy, lung allografts are the exception. Aerosolized pharmacologic agents have direct access to the lung, and there is extensive experience in the use of inhaled β-agonists and nebulized antibiotics. In animal models, aerosolized cyclosporine has been demonstrated to be safe and more effective than systemic cyclosporine in preventing graft rejection (Dowling R. D., 1990, Surgery, 108:198; Zenati, M., 1991, Eur. J. Cardiothor. Surg., 5:266; Keenan, R. J. et al., 1992, Transplantation 53:20-25; Rabinowich H., 1988, Transplant Proc., 20:836). Local delivery of aerosolized cyclosporine has been effectively used to deliver cyclosporine to the lungs of patients with severe chronic graft rejection that was refractory to all previous attempts at control (Burckart, G. J., 1989, J Clin. Pharmaco. 29: 860; Iacono, A. T., et al., 1996, Am. J. Resp. Crit. Care Med., 153:1451-1455). In addition aerosolized cyclosporine was effective as therapy for refractory acute rejection in lung-transplant subjects unresponsive to conventional therapy (O'Riordan, T. G., et al., 1995, Am. J. Respir. Crit. Care Med. 151:516; Iacono, A. T., et al., 1997, Am. J. Resp. Crit. Care Med. 155:1690-1698; Keenen, R. J., et al., 1997, J. Thorac. Cardiovasc. Surg., 1134:335-341).